Bcl-xL gain of function and p19ARF loss of function cooperate oncogenically with Myc in vivo by distinct mechanisms
Bcl-xL gain of function and p19ARF loss of function cooperate oncogenically with Myc in vivo by distinct mechanisms
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DOI：
10.1016/j.ccr.2006.06.017
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发表时间：
2006-08-01
期刊：
影响因子：
50.3
通讯作者：
Evan, Gerard I.
中科院分区：
文献类型：
--
作者：
Finch, Andrew;Prescott, Julia;Evan, Gerard I.
Bcl-x（L）的过表达、p19（ARF）的缺失和p53的缺失都加速了Myc肿瘤的发生。所有三种病变都涉及抑制Myc诱导的细胞凋亡，这表明这是它们与Myc协同作用的共同机制。然而，使用Myc诱导的肿瘤发生的急性可切换模型，我们证明了每个病变在体内通过不同的机制与Myc合作。当Bcl-x（L）阻断Myc诱导的细胞凋亡时，p19 ARF的失活增强了它，然而，这种细胞凋亡的增加与Myc诱导的细胞增殖的增加相匹配。p53失活具有两种病变的共同特征，部分抑制细胞凋亡，同时增加增殖。Bcl-x（L）和p19（ARF）的丢失共同协同作用，进一步加速Myc肿瘤的发生。因此，不同的病变与Myc的致癌合作，通过离散的机制，可以自己与对方协同。
Overexpression of Bcl-x(L), loss of p19(ARF), and loss of p53 all accelerate Myc oncogenesis. All three lesions are implicated in suppressing Myc-induced apoptosis, suggesting that this is a common mechanism by which they synergize with Myc. However, using an acutely switchable model of Myc-induced tumorigenesis, we demonstrate that each lesion cooperates with Myc in vivo by a distinct mechanism. While Bcl-x(L) blocks Myc-induced apoptosis, inactivation of p19ARF enhances it. However, this increase in apoptosis is matched by increased Myc-induced proliferation. p53 inactivation shares features of both lesions, partially suppressing apoptosis while augmenting proliferation. Bcl-x(L) and p19(ARF)loss together synergize to further accelerate Myc oncogenesis. Thus, differing lesions cooperate oncogenically with Myc by discrete mechanisms that can themselves synergize with each other.